In silico and in vivo evaluations of fisetin and fisetin-loaded nanosuspension on monoamine oxidase inhibition in Aβ(25–35) induced dementia in mice model

Background

Amyloid beta (Aβ) plaques on the extracellular matrix and intracellular neurofibrillary tangles comprise the key indicative pathology of Alzheimer's disease (AD). Fisetin, an antioxidant bioactive compound having pharmacotherapeutic effects is applied by traditional Chinese medicine (TCM) such as Toxicodendron vernicifum (Chinese lacquer tree), Cotinus coggygria Scop, Gan Shuang granulates and formula of Acacia catechu-Scutellariae Radix. Nevertheless, fisetin has constraints such as low oral bioavailability, insignificant aqueous solubility and high hepatic metabolisms.

Objective

This investigation aimed to envisage the effects of fisetin and its optimised nanoformulation on Aβ_(25–35) desirous neurotoxicity in mice through deciphering inhibitory actions against monoamine oxidase A and B (MAO-A and B) enzymes following molecular docking.

Methods

Molecular docking with MAO-A and B enzymes were accomplished by AMDock's integrated AutoDock Tools (ADT) scripts. For in vivo studies, fisetin nanosuspension was prepared by nanoprecipitation method and evaluated for standard characterization. 10 and 20 mg/kg of fisetin and 10 mg/kg of fisetin nanosuspension were given once daily to mice for 21 days. On the 15th day, the mice were challenged with Aβ_(25–35) by intracerebroventricular injection (ICV) and behavioural tests (open field and elevated plus maze) were performed on the 20th day. Biochemical and histology were examined in brain tissues.

Results

Fisetin docked to the catalytic positions of MAO-A and B, unveiling good binding scores and molecular interactions with amino acid residues for inhibition activities. Fisetin nanosuspension has average particle size (225.4 ± 2.95 nm) with low polydispersity index (0.19) and standard zeta potential (-19.13 ± 1.17 mV). Findings showed that fisetin increased locomotor activity and reduced anxiety-like behaviour. Fisetin and its nanosuspension significantly reduced the concentration of MAO-A (P < 0.01) and MAO-B enzymes suggesting a potential neuroprotection effect in Aβ peptide-induced amnesia in mice.

Conclusion

Fisetin with optimized bioavailability, effectively exhibits neuroprotection through molecular interactions of MAO enzymes. Further investigations affidavits the neuroprotection through bidirectional pathways related to biogenic amines and their deamination on Aβ stress conditions.